Process for the preparation of 17beta-oxy-genated-delta4, 9(10)-estradiene-3-one



United States Patent The invention relates to novel estradienes having the wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to '18 carbon atoms. The invention further relates to novel processes for the preparation of said estradienes and the intermediates thereof.

The estradienes of Formula I have interesting pharmacological properties, and are particularly useful as anabolisants. The said estradienes are also useful intermediates for the preparation of A -estradiene-i1B- ol-3-one and its esters which are used to prepare estradiol by isomerization as disclosed in the commonly-assigned, copending US. application Serial No. 57,136, filed September 20, 1960.

It is an object of the invention to provide the novel steroids, A 0 -estradiene-17,8-ol-3-one and its esters.

It is another object of the invention to provide novel processes for the preparation of the novel estradienes of Formu a lt is an additional object of the invention to provide novel intermediates for the novel estradienes of Formula It is a further object of the invention to provide an improved process for the preparation of A -estradi- .ene-l'lfl-ol-S-one and its esters.

These and other objects and advantages of the invention will become obvious from the following detailed description.

The novel compounds of the invention have the for- 3,685,698 Patented Apr. 9, 1963 2 acid; aryl alkanoic acids such as phenyl propionic acid; cycloalkanoic acids such as hexahydrobenzoic acid and hexahydroterephthalic acid; and phenyl carboxylic acids such as benzoic acid and 3,5-dinitrobenzoic acid.

One process for the preparation of compounds of Formula 1 comprises reacting a secondary amine having the formula E (II) wherein R and R are lower alkyl and when taken together with the nitrogen atom are selected from the group consisting of pyrrolidino, piperidyl and morpholino with a compound havingthe formula wherein R has the above definition to form a 3-enamine wherein R, R and R have the above definition, hydrolyzing the latter a short time with a weak lower alkanoic acid such as acetic acid or propionic acid to form a 17fl-oxygenated-A -estradiene-3-one of Formula I and recover'mg the latter. The compounds of Formula I may then be isomerized with strong mineral acids to form 13 -estradiene-17fi-ol-3-one or its esters.

Another process for the preparation of the estradienes of Formula 1 comprises reacting a compound of the formula wherein R has the above definition, prepared according to copending US. application Serial No. 57,136, now US. Patent No. 3,056,811, with a secondary amine of Formula -II to form the corresponding 3-enamino-l75- oxygenated-A -estratriene of Formula 1V, hydrolyzing the latter a short time with a weak alkanoic acid to form the corresponding 17fl-oxygenated-A ,estradiene-3-one of Formula I and recovering the latter.

The improved process for the preparation of l7p3-oxygenated-A -estradiene-Zv-ones of Formula V comprises reacting a compound of Formula III with a secondary amine of Formula II to form a 3-enamino-17B-oxygenated-A -estratriene of Formula IV, and reacting the latter a prolonged time with acetic acid.

The reaction schemes of the invention are illustrated in Table I.

3 TABLE I O (III) R Rd W) wherein R is selected from the group consisting ofi hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms and R and R may be lower alkyl and when taken together are selected from the group consisting of pyrrolidyl, piperidyl and morpholino. e

The compounds of Formula III are 3-methyl-7-oxo-8- (3 oxobutyl) 3,4 -(3'- oxygenated l',2 cyclopentano)-A -octa.hydronaphthalenes and may be prepared as described in commonly-assigned, copending application Serial No. 36,171 filed June 15, 1960, now US. Patent No. 3,019,252.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

Example I PREPARATION on ivennnzoynoxr-nw fl ESTRADIENE-3-ONE Step A--Preparation of 1 713-benzoyloxy-3-pyrrolidino- A -eSflatrin.-Th61'6 was heated to the boiling point for a period of 4 minutes a mixture of 10 cc. of pure methanol, 1 gm. of -3/3-methyl-7-oxo-8;3-(3'-oxobutyl) 3u,4B (3' benzoyloxy 1,2' cyclopentano) A -octahydronaphtha1ene and 1 cc. of pyrrolidine. The reaction was allowed to remain overnight at room temperature and cooled for about 1 more hour in a refrigerator before vacuum filtering. Afiter vacuum filtering, washing with iced methanol and drying, 980 mg. (being a yield of 90%) of 17,8-benzoyloxy-3-pyrrolidino-A -estratriene were obtained, sufliciently pure for its use in step 13.

For analysis, the product was recrystallized by dissolution in lukewarm benzene and methanol added thereto. After drying, the product had a melting point of 148 C. and a specific rotation [a] =+261 (c.=0.72% in benzene).

The ultraviolet spectra determined in ether showed:

A 228 m (e=26,500) Others A at 273,280 and 297 nm, and A 348 m (e=23,000)

The clear yellow product was soluble in 3 volumes of lukewarm benzene, slightly soluble in methanol and in ether.

Analysis:C H O N: Molecular weight=429.58. Calculated: C, 81.07%; H. 8.21%; N, 3.26%. Found: C, 80.9%; H, 8.2%; N, 3.2%.

This compound is not described in the literature.

Step BPreparati0n of 17p-benz0yl0xy-A -estradiene 3 one.(a)0.68 gm. of the compound prepared in Step A were dissolved in 0.68 cc. of pure acetic acid under agitation as rapidly as possible. After the product was dissolved, 6.8 cc. of distilled water were immediately added. Crystallization of l7fi-benzoyloxy- -estradiene-3-one commenced very soon. The mixture was allowed to stand for a quarter of an hour at room temperature and the precipitate formed was vacuum filtered, washed with water and dried. The raw precipitate obtained was purified by recrystallization from boiling acetone. The product had a melting point 015 173-174" C., and a specific rotation [a] =-[106.4 (c.=1% in chloroform). A second recrystallization from acetone or isopropyl ether did not change the melting point.

The ultraviolet spectra determined in ethanol shows:

A 234 m (e=31,550) A 280 m (6 920) The product was soluble in warm acetone and in warm isopropyl ether, and insoluble in water.

Its infrared spectra confirmed the absence of conjugated ketone function and the presence of the benzoate function.

Analysis.--C H O Molecular weight=376.5. Calculated: C, 79.75%; H, 7.5%. Found: C, 79.5%;

| This compound is not described in the literature. A -estradiene-17fl-ol-3-one is obtained :by the same suite of reactions.

Example I1 PREPARATION OF 17fl-BENZOYLOXY-N- ESTRADIENE-3-ONE 0.7 gm. of 17fi-benzoyloxy-3-pyrrolidino -A estratriene were dissolved in 0.7 cc. of acetic acid and the reaction mixture allowed to stand at 20-25 C. for a period of 30 minutes. 7 cc. of distilled water were added and the reaction mixture allowed to stand for a quarter of an hour. A little of quantity product was separated and was vacuum filtered and washed with water. It represented 50 mg. (an 8% yield) of 17fi-benzoyloxy- A -eStradiene-S-One.

The filtration liquors and the wash liquor were combined and brought to a pH of 9 by slow addition of sowas purified by recrystallization from acetone.

dium hydroxide solution under agitation. An abundant precipitate was formed which was vacuum filtered, washed with water and dried. 530 mg. -(a yield of 87%) of 175- benzoyloxy-A -estradiene-3-one were obtained which The product had a melting point of 163-164 C., and did not give a depression of the melting point when mixed with 175- 6 benzoyloxy-A -estradiene-S-one obtained starting from l7-benzoyloxy-19-nor-A -androstcne-5-ol-3-one.

By heating with methanolic pyrrolidine, 17p-benzoyloxy-A -estradiene-3-one furnished 17/3-benzoyloxy-3- pyrrolidino-A -estratriene described in step 1 of the example.

Example III ISOMERIZATION OF l'lB-BENZOYLOXY-A ESTRA- DIENE-3-0NE INTO l'l'fl-BENZOYLOXY-A -ESTRA- DIENE-iZ-ONE 1 gm. of 17p-benzoyloxy-A -estradiene-B-one was dissolved in 30 cc. of acetic acid containing 10% of perchloric acid (27 cc. of acetic acid plus 3 cc. of 6 3% perchloric acid) and the solution was allowed to stand for a period of 30 minutes at a temperature of 25 C.

After the addition of 300 cc. of water, a gummy product was obtained which was extracted three times with 50 cc. of methylene chloride. The organic phases were combined, washed with 2 0 cc. of a saturated solution of sodium bicarbonate then twice with 100 cc. of Water until the wash waters were neutral. The product remaining was dried. A gum was obtained which was made to crystallize by the addition of 2 cc. of isopropyl ether. The solution was cooled minutes and vacuum filtered. The precipitate was washed twice vw'th 2 cc. of cold isopropyl ether. 17fi-benzoyloxy-A -estradiene-3-one melting at 163-164 C. was obtained with an almost quantitative yield.

The present application is a divisional application of application Serial No. 124,317, filed July' 17, 1961, now United States Patent No. 3,052,672.

Various modifications of the processes of the present invention may be made without departing from the spirit or scope thereof, and it is to be understood that the invention be limited only as defined in the appended claims.

We claim:

1. A process for the preparation of lbs-oxygenated- A -estradiene-S-one having the formula [JOB c wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms which comprises reacting a secondary amine selected from the group consisting of di-lower alkyl amines, pyrrolidine, piperidine and morpholine and a compound having the formula IJOR ene having the formula 1 [JOB wherein R has the above definition and R and R are lower alkyl and when taken together with the nitrogen atom are selected from the group consisting of pyrrolidino, piperidino and monpholino, hydrolysing the latter a prolonged time, with a lower alkanoic acid to form the said 17fl-oxygenated-A -estradiene-3-one and recovering the latter.

2. The process of claim 1 wherein the secondary amine is pyrrolidine, R is a benzoyloxy radical and the lower alkanoic acid in acetic acid.

References Cited in the file of this patent UNITED STATES PATENTS 3,052,672 Nomine et a1. Sept. 4, 1962 

1. A PROCESS FOR THE PREPARATION OF 17B-OXYGENATED$4,9(10)-ESTRADIENE-3-ONE HAVING THE FORMULA 